The kidney is essential not only for its ability to filter toxins and excess nutrients from the blood, but also for its ability to synthesize the active form of vitamin D3, 1,25-dihydroxyvitamin D3 [1,25(OH)2D3]. In patients with chronic kidney disease, both these functions are impaired. Consequently, levels of 1,25(OH)2D3 decline, leading to hypocalcemia. Meanwhile, nutrients, particularly phosphorus, accumulate in the blood. Hypocalcemia and hyperphosphatemia are both potent stimulators of parathyroid hormone (PTH) secretion. Over time, hyperparathyroidism in the presence of even trace amounts of 1,25(OH)2D3 cause excess bone resorption, leading to a condition known as renal osteodystrophy (1). In addition to dialysis treatment, it is essential to suppress excessive PTH levels and reduce phosphorus in the blood to prevent this condition.
Vitamin D analogs, such as 1,25-dihydroxy-19-nor-vitamin D2 (19-nor-D2, Zemplar®, Abbott Laboratories, Abbott Park, Ill.) and 1 α-hydroxyvitamin D2 [1α-(OH)D2, Hectorol®, Genzyme Corporation/Bone Care International, Middleton, WIS.] are administered to patients to suppress hyperparathyroidism. Although these analogs are effective at suppressing PTH levels, they still retain some ability to stimulate intestinal calcium and phosphate absorption, which may be problematic when the analogs are administered at high doses or in conjunction with calcium-based oral phosphate binders (1).
Reducing the absorption of phosphorus from foods is also a challenging task. The current Recommended Dietary Allowance (RDA) for phosphorus is 700 mg per day (2), but most Americans consume 1000-1600 mg of phosphorus each day (3). Dietary phosphorus restriction is not very effective due to the richness of phosphorus in foods such as dairy products, meat, fish, eggs, nuts, grains, baked goods, and soft drinks. Moreover, it is estimated that 65-75% of consumed phosphorus is absorbed (4). As a result, oral phosphate binders are often administered with meals to reduce the absorption of phosphorus.
In the 1970s, aluminum-based binders were extensively used to bind phosphate from foods, but the use was severely reduced after aluminum was shown to accumulate in patients causing toxic side-effects such as bone disease, encephalopathy, and anemia (5). Calcium acetate (PhosLo, Nabi Pharmaceuticals, Boca Raton, Fla.) was then developed as an alternative to aluminum-based binders, but must be administered at high levels to be effective. Furthermore, when administered in conjunction with 1,25(OH)2D3 or a vitamin D analog, the oral calcium may contribute to hypercalcemia (5). Recently, lanthanum carbonate (Fosrenol®, Shire US Incorporated, Wayne, Pa.) was approved by the FDA for use as an oral phosphate binder. Although effective, its low rate of absorption raises some speculation that toxicity issues may arise with long-term use (6).
Sevelamer hydrochloride (Renagel®, Genzyme Corporation, Cambridge, Mass.), a phosphate-binding polymer, has been successfully used to reduce absorption of dietary phosphorus with fewer side effects than aluminum or calcium (7). Unfortunately, sevelamer hydrochloride is costly (average cost of $4400 per year in 2002) and must be taken in large quantities (average dose of 6.5 g per day) to be effective (8).
Dendrimers are well known therapeutic tools. Dendrimers have been used in applications including imaging agents, nano-scaffolds, antitumor drugs, gene transfection agents, nanoscale containers and biomimetic artificial proteins (14). However, therapeutic dendrimer compositions that bind phosphate, thereby treating hypocalcemia, hyperphosphatemia and chronic kidney disease, are not known.
Thus, a need exists for dendrimeric compositions containing varying amounts of free amines that can bind phosphate and inhibit its absorption in vivo.